Ether Lipids Research Articles

Integrated multi-omics characterization across clinically relevant subgroups of long COVID

Abstract With SARS-CoV-2 became regional epidemics, substantial amount of patients suffers from post-acute sequelae of COVID-19 (PASC, aka long COVID). Exploring the pathogenesis and especially the heterogenicity features of long COVID subgroups is of paramount importance for etiology understandings. In this study, through integrative multi-omics analyses encompassing transcriptomics, proteomics, and metabolomics, long COVID patients exhibited overall elevated MAPK pathway activation, while patients recovered from long COVID showed down-regulation of this response. Long COVID heterogenicity is described by multi-omics distinct signatures for each subgroup. Multisystemic (MULTI) symptoms subgroup is characterized by enhanced glycerophospholipid and ether lipid metabolism, Neurological (NEU) by augmented glycoprotein synthesis metabolism, Cardio cerebral (CACRB) by increased pyruvate metabolism and suppressed macrophage polarization, Musculoskeletal + Systemic (MSK + SYST) by elevated glycerophospholipid metabolism, and Cardiopulmonary (CAPM) by inhibited NF-κB signaling pathways. ABHD17A, CSNK1D, PSME4 and SYVN1 were general long COVID combination biomarkers, while CRH (MULTI), FPGT (NEU), CBX6 (CACRB) and RBBP4 (CAPM) were selected as serum-specific subgroup proteins. Our study provides commonly shared and distinct pathophysiology explanation underpinning PASC, paving the way for the future diagnosis and therapeutic interventions.

Proteomic biomarkers and biological mechanisms associated with atrial fibrillation in heart failure patients

Abstract Background Atrial fibrillation (AF) and heart failure (HF) are intertwined conditions with high mortality rates and large impact on quality of life, and their coexistence is increasingly prevalent. Both conditions influence each other’s development and progression, and share many risk-factors—such as hypertension, obesity, diabetes mellitus and ischaemic heart disease. Moreover, their combined presence further increases the risk of hospitalization and mortality. The biological mechanisms at play in HF patients with AF may therefore differ from those in HF patients without AF. Purpose We aimed to describe the differences in pathophysiological pathways in HF patients with versus without AF, by identifying biomarkers associated with AF from a panel of 4210 circulating proteins and subsequently examining biological mechanisms related to these biomarkers. Methods We examined 377 ambulant HF patients with reduced ejection fraction from a longitudinal cohort study. We measured 4210 circulating proteins in baseline blood samples using an aptamer-based multiplex proteomic approach. Associations between AF (known AF history or AF on the baseline ECG) and the proteins were assessed using linear regression models adjusted for age, sex, kidney function and duration of HF at baseline. Associations of proteins significantly related to AF, with biological processes, were assessed using network-based clustering and subsequent enrichment analysis. Results The median [25th, 75th percentile] age was 64 [55, 72], 73% [274/377] were male, 28% [104/375] had NYHA-class III or IV, and 37% [139/377] had AF (either AF history: 36% [137/377] or AF on baseline ECG: 8% [30/374]). We found 71 proteins significantly associated with AF (FDR<0.05), including well-studied (e.g. troponin T, IGFBP7, MFAP4, BMP10, angiopoietin 2) and lesser studied (e.g. olfactomedin−like protein 3, keratocan, basigin) proteins in the AF domain. Our pathway analysis revealed clusters of proteins related to various underlying mechanisms, such as axon guidance, elastic fibre assembly, macrophage derived foam cell differentiation, ether lipid metabolism and amyloid-beta binding. Overviews of the significantly associated proteins and related biological mechanisms are provided in Figures 1 and 2. Conclusion HF patients with AF have distinct proteomic profiles and these differences are related to various biological mechanisms, many of which can be associated with atrial remodelling. This study provides an overview of the biological mechanisms behind AF in HF, confirms prior findings regarding AF-related proteins, and could guide future research in novel treatment targets and HF-AF management.Figure 1:Proteins associated with AFFigure 2:Biological mechanisms

B cell expression of the enzyme PexRAP, an intermediary in ether lipid biosynthesis, promotes antibody responses and germinal center size.

The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states as well as Ab diversification. However, there is little information about lymphoid cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis, including a major class of membrane phospholipids. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens. However, it was not clear if biosynthesis in B cells was a basis for this finding, or whether such cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, the product of the Dhrs7b gene. Using combinations of IMS and immunization experiments in mouse models with inducible Dhrs7b loss-of-function, we now show that B lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed a Dhrs7b -dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.

Wheat bran oil ameliorates high-fat diet-induced obesity in rats with alterations in gut microbiota and liver metabolite profile

BackgroundObesity is one of the public health issues that seriously threatens human health. This study aimed to investigate the effects of wheat bran oil (WBO) on body weight and fat/lipid accumulation in high-fat diet (HFD)-induced obese rats and further explore the possible mechanisms by microbiome and metabolome analyses.MethodsFifty Sprague-Dawley (SD) rats were fed either a normal chow diet (B group, n = 10) or HFD (n = 40) for 14 weeks to establish an obesity model. The HFD-induced obese rats were further divided into four groups and given WBO at 0 mL/kg (M group), 1.25 mL/kg (WBO-L group), 2.5 mL/kg (WBO-M group), and 5 mL/kg (WBO-H group) by oral gavage for 9 weeks. The body weight of rats was weighed weekly. The gut microbiota structure was analyzed using 16 S rDNA high-throughput sequencing. The liver metabolite profile was determined using UHPLC-QE-MS non-target metabolomics technology.ResultsIn this study, WBO treatment reduced body weight gain, fat and lipid accumulation, and ameliorated hepatic steatosis and inflammation. WBO treatment increased the relative abundance of Romboutsia and Allobaculum and decreased that of Candidatus_Saccharimonas, Alloprevotella, Rikenellaceae_RC9_gut_group, Alistipes, Parabacteroides, UCG-005, Helicobacter, Colidextribacter, and Parasutterella compared with the M group. A total of 22 liver metabolites were significantly altered by WBO treatment, which were mainly involved in taurine and hypotaurine metabolism, nicotinate and nicotunamide metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and ether lipid metabolism.ConclusionsWBO alleviated body weight gain and fat/lipid accumulation in HFD-induced obese rats, which may be related to altered gut microbiota and liver metabolites.

Repetitive transcranial magnetic stimulation elicits weight loss and improved insulin sensitivity in type 2 diabetic rats.

Type 2 diabetes (T2D) accounts for the majority of diabetes incidences and remains a widespread global chronic disorder. Apart from early lifestyle changes, intervention options for T2D are mainly pharmaceutical. Repetitive transcranial magnetic stimulation (rTMS) has been approved by the FDA as a therapeutic intervention option for major depressive disorders, with further studies also indicating its role in energy metabolism and appetite. Considering its safe and non-invasive properties, we evaluated the effects of rTMS on systemic metabolism using T2D rats. We observed that rTMS improved glucose tolerance and insulin sensitivity in T2D rats after a 10-day exposure. Improved systemic insulin sensitivity was maintained after a 21-day treatment period, accompanied by modest yet significant weight loss. Circulating serum lipid levels, including those of cholesteryl ester, tryglyceride and ceramides, were also reduced following rTMS application. RNA-seq analyses further revealed a changed expression profile of hepatic genes that are related to sterol production and fatty acid metabolism. Altered expression of hypothalamic genes that are related to appetite regulation, neural activity and ether lipid metabolism were also implicated. In summary, our data report a positive impact of rTMS on systemic insulin sensitivity and weight management of T2D rats. The underlying mechanisms via which rTMS regulates systemic metabolic parameters partially involve lipid utilization in the periphery as well as central regulation of energy intake and lipid metabolism.

Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site.

Host-related factors highly regulate the increased circulation of neutrophils during Leishmania infection. Platelet-derived Dickkopf-1 (DKK1) is established as a high-affinity ligand to LRP6. Recently, we demonstrated that DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to the draining lymph node and Th2 differentiation during Leishmania infection, suggesting the potential involvement of the DKK1-LRP6 signalling pathway in neutrophil migration in infectious diseases. In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6NKO) or BALB/c mice deficient in both PMN LRP6 and platelet DKK1 (LRP6NKO DKK1PKO). Relative to the infected wild-type BALB/c mice, reduced neutrophil activation at the infection site of LRP6NKO or LRP6NKO DKK1PKO mice was noted. The neutrophils obtained from either infected LRP6NKO or LRP6NKO DKK1PKO mice additionally showed a high level of apoptosis. Notably, the level of LRP6 expressing neutrophils was elevated in infected BALB/c mice. Relative to infected BALB/c mice, a significant reduction in parasite load was observed in both LRP6NKO and LRP6NKO DKK1PKO infected mice. Notably, DKK1 levels were comparable in the LRP6NKO and BALB/c mice in response to infection, indicating that PMN activation is the major pathway for DKK1 in promoting parasitemia. Parasite-specific components also play a crucial role in modulating neutrophil circulation in Leishmania disease. Thus, we further determine the contribution of Leishmania membrane components in the migration of neutrophils to the infection site using null mutants deficient in LPG synthesis (Δlpg1- ) or lacking all ether phospholipids (plasmalogens, LPG, and GIPLs) synthesis (Δads1- ). Relative to the WT controls, Δads1- parasite-infected mice showed a sustained decrease in neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while neutrophils returned to normal in Δlpg1- parasite-infected mice after day 3 PI. Our results suggest that DKK1 signalling and Leishmania pathogen-associated molecular patterns appear to regulate the migration and sustenance of viable activated neutrophils in the infection site resulting in chronic type 2 cell-mediated inflammation.

Non-targeted metabolomics and pseudo-targeted lipidomics combined with gut microbes reveal the protective effects of Causonis japonica (Thunb.) Raf. in ulcerative colitis mice.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent inflammatory tissue damage to the intestinal mucosa and forming intestinal epithelial ulcers. It is one of the most intractable diseases in the world. To date, the mechanism is unclear. Causonis japonica (Thunb.) Raf. (Wu Lianmei in Chinese; WLM), a traditional Chinese medicine, which has a long history as an anti-inflammatory, but its effect on UC was unconfirmed yet. Therefore, we established a dextran sodium sulfate (DSS)-induced UC mice model and evaluated the therapeutic effect of WLM extract. The results indicated that WLM inhibits DSS-induced inflammatory response in colitis in vivo, decrease DSS-induced clinical manifestations, reverses colon length shortening, and reduces tissue damage. The results of ELISA kits suggested that WLM could reverse the levels of DSS-induced inflammatory factors. To explore the mechanism of WLM in treating DSS-induced UC, 1H NMR and UHPLC-Q/Orbitrap MS were used to perform non-targeted metabolomics analysis; 21 differential metabolites in colon tissues were closely related to UC. Meanwhile, the pseudo-targeted lipidomics based on UHPLC-Q/Trap MS was used to analyze lipid metabolism disorders, and 60 differential lipid compounds were screened. These differential compounds were mainly involved in glycerophospholipid, arachidonic acid, glycerolipid, citric acid, tyrosine, and ether lipid metabolisms. The analysis of gut microbial showed that WLM may improve the symptoms of UC mice by reducing the abundance of Helicobacter and Streptococcus and increasing the abundance of Limosilactobacillus and Akkermansia. Moreover, the real-time qPCR results showed that WLM extract could decrease the mRNA levels of inflammatory factors and may be associated with protecting the integrity of intestinal mucosal barrier by destroying in vivo metabolic pathways, especially by regulating energy and lipid metabolisms and reducing inflammatory reactions. It provides a beneficial reference for studying WLM to elucidate the therapeutic mechanism of UC.

Nosema ceranae infection reduces the fat body lipid reserves in the honeybee Apis mellifera

Nosema ceranae is an intestinal parasite frequently found in Apis mellifera colonies. This parasite belongs to Microsporidia, a group of obligate intracellular parasites known to be strongly dependent on their host for energy and resources. Previous studies have shown that N. ceranae could alter several metabolic pathways, including those involved in the nutrient storage. To explore the impact of N. ceranae on the fat body reserves, newly emerged summer bees were experimentally infected, and we measured (1) the lipid percentage of the abdominal fat body at 2-, 7- and 14-days post-inoculation (p.i.) using diethyl ether lipid extraction, (2) the triglyceride and protein concentrations by spectrophotometric assay methods, and (3) the amount of intracellular lipid droplets in trophocytes at 14- and 21-days p.i. using Nile Red staining. Comparing the three methods used to evaluate lipid stores, our data revealed that Nile Red staining seemed to be the simplest, fastest and reliable method. Our results first revealed that the percentage of fat body lipids significantly decreased in infected bees at D14 p.i. The protein stores did not seem to be affected by the infection, while triglyceride concentration was reduced by 30% and lipid droplet amount by 50% at D14 p.i. Finally, a similar decrease in lipid droplet reserves in response to N. ceranae infection was observed in bees collected in fall.

Glial peroxisome dysfunction induces axonal swelling and neuroinflammation in Drosophila.

Glial cells are known to influence neuronal functions through glia-neuron communication. The present study aims to elucidate the mechanism behind peroxisome-mediated glia-neuron communication using Drosophila neuromuscular junction (NMJ) as a model system. We observe a high abundance of peroxisomes in the abdominal NMJ of adult Drosophila. Interestingly, glia-specific knockdown of peroxisome import receptor protein, Pex5, significantly increases axonal area and volume and leads to axon swelling. The enlarged axonal structure is likely deleterious, as the flies with glia-specific knockdown of Pex5 exhibit age-dependent locomotion defects. In addition, impaired peroxisomal ether lipid biosynthesis in glial cells also induces axon swelling. Consistent with our previous work, defective peroxisomal import function upregulates pro-inflammatory cytokine upd3 in glial cells, while glia-specific overexpression of upd3 induces axonal swelling. Furthermore, motor neuron-specific activation of the JAK-STAT pathway through hop overexpression results in axon swelling. Our findings demonstrated that impairment of glial peroxisomes alters axonal morphology, neuroinflammation, and motor neuron function.

Selenium polysaccharide form sweet corn cob mediated hypoglycemic effects in vitro and untargeted metabolomics study on type 2 diabetes

Type 2 diabetes mellitus (T2D) causes complications due to metabolic disorders besides increasing blood glucose. Sweet corn cob selenium polysaccharide (SeSCP) is a complex of Se with Sweet corn cob polysaccharide that has good hypoglycemic efficacy, but its effect on T2D metabolism has not been determined. In this study, the hypoglycemic effect of SeSCP was investigated by in vitro and in vivo experiments, and the levels of metabolites in feces were analyzed in a high-fat diet and STZ-induced T2D mouse model by Liquid chromatography-mass spectrometry (LC-MS). The results indicated that SeSCP regulates α-amylase and α-glucosidase through competitive reversible inhibition, and the reaction is spontaneous, driven by van der Waals forces and hydrogen bonding. In vivo, SeSCP modulates glucose transport decreasing glucose entry into the bloodstream. The metabolites mainly affected by SeSCP-MC were adenine, LysoPA (0:0/18:2(9Z, 12Z)), cysteine-S-sulfate, and demeclocycline (hydrochloride) metabolites. SeSCP interfered with β-alanine metabolism, starch and sucrose metabolism, ether lipid metabolism, glycerophospholipid metabolism, glyoxylate and dicarboxylate metabolism, pantothenate and CoA biosynthesis, etc. Additionally, SeSCP exhibited more effective metabolic interventions than metformin and SCP. Therefore, SeSCP can reduce complications while improving T2D blood glucose.

Biocatalytic Ether Lipid Synthesis by an Archaeal Glycerolprenylase

AbstractAlthough ethers are common in secondary natural products, they are an underrepresented functional group in primary metabolism. As such, there are comparably few enzymes capable of constructing ether bonds in a general fashion. However, such enzymes are highly sought after for synthetic applications as they typically operate with higher regioselectivity and under milder conditions than traditional organochemical approaches. To expand the repertoire of well characterized ether synthases, we herein report on a promiscuous archaeal prenyltransferase from the scarcely researched family of geranylgeranylglyceryl phosphate synthases (GGGPSs or G3PSs). We show that the ultrastable Archaeoglobus fulgidus G3PS makes various (E)‐ and (Z)‐configured prenyl glycerol ethers from the corresponding pyrophosphates while exerting perfect control over the configuration at the glycerol unit. Based on experimental and computational data, we propose a mechanism for this enzyme which involves an intermediary prenyl carbocation equivalent. As such, this study provides the fundamental understanding and methods to introduce G3PSs into the biocatalytic alkylation toolbox.

Biocatalytic Ether Lipid Synthesis by an Archaeal Glycerolprenylase.

Although ethers are common in secondary natural products, they are an underrepresented functional group in primary metabolism. As such, there are comparably few enzymes capable of constructing ether bonds in a general fashion. However, such enzymes are highly sought after for synthetic applications as they typically operate with higher regioselectivity and under milder conditions than traditional organochemical approaches. To expand the repertoire of well characterized ether synthases, we herein report on a promiscuous archaeal prenyltransferase from the scarcely researched family of geranylgeranylglyceryl phosphate synthases (GGGPSs or G3PSs). We show that the ultrastable Archaeoglobus fulgidus G3PS makes various (E)- and (Z)-configured prenyl glycerol ethers from the corresponding pyrophosphates while exerting perfect control over the configuration at the glycerol unit. Based on experimental and computational data, we propose a mechanism for this enzyme which involves an intermediary prenyl carbocation equivalent. As such, this study provides the fundamental understanding and methods to introduce G3PSs into the biocatalytic alkylation toolbox.

Uncovering lipid dynamics in Staphylococcus aureus osteomyelitis using multimodal imaging mass spectrometry

Osteomyelitis occurs when Staphylococcus aureus invades the bone microenvironment, resulting in a bone marrow abscess with a spatially defined architecture of cells and biomolecules. Imaging mass spectrometry and microscopy are tools that can be employed to interrogate the lipidome of S.aureus-infected murine femurs and reveal metabolic and signaling consequences of infection. Here, nearly 250 lipids were spatially mapped to healthy and infection-associated morphological features throughout the femur, establishing composition profiles for tissue types. Ether lipids and arachidonoyl lipids were altered between cells and tissue structures in abscesses, suggesting their roles in abscess formation and inflammatory signaling. Sterols, triglycerides, bis(monoacylglycero)phosphates, and gangliosides possessed ring-like distributions throughout the abscess, suggesting a hypothesized dysregulation of lipid metabolism in a population of cells that cannot be discerned with traditional microscopy. These data provide insight into the signaling function and metabolism of cells in the fibrotic border of abscesses, likely characteristic of lipid-laden macrophages.

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

Unraveling the Molecular Landscape of SCN1A Gene Knockout in Cerebral Organoids: A Multiomics Approach Utilizing Proteomics, Lipidomics, and Transcriptomics.

This study investigates the impact of sodium channel protein type 1 subunit alpha (SCN1A) gene knockout (SCN1A KO) on brain development and function using cerebral organoids coupled with a multiomics approach. From comprehensive omics analyses, we found that SCN1A KO organoids exhibit decreased growth, dysregulated neurotransmitter levels, and altered lipidomic, proteomic, and transcriptomic profiles compared to controls under matrix-free differentiation conditions. Neurochemical analysis reveals reduced levels of key neurotransmitters, and lipidomic analysis highlights changes in ether phospholipids and sphingomyelin. Furthermore, quantitative profiling of the SCN1A KO organoid proteome shows perturbations in cholesterol metabolism and sodium ion transportation, potentially affecting synaptic transmission. These findings suggest dysregulation of cholesterol metabolism and sodium ion transport, with implications for synaptic transmission. Overall, these insights shed light on the molecular mechanisms underlying SCN1A-associated disorders, such as Dravet syndrome, and offer potential avenues for therapeutic intervention.

Metabolic changes induced by heavy metal copper exposure in human ovarian granulosa cells

Copper (Cu) is a common heavy metal and a hazardous environmental pollutant. Emerging epidemiological evidence suggests that Cu exposure is associated with female infertility, especially ovarian dysfunction. However, the mechanisms underlying ovarian toxicity remain poorly understood. Granulosa cells play crucial roles in follicle development and are the main target cells of environmental pollutants for ovarian toxicity. In this study, we investigated the effects of Cu exposure on human granulosa (KGN) cells by using cell biology and metabolomics methods, and explored the molecular mechanisms of Cu-induced cytotoxicity. We found that Cu reduced cell viability in a dose- and time-dependent manner. Then, metabolomic analyses led to the identification of 279, 368 and 466 differentially expressed metabolites (DEMs) in KGN cells exposed to 10, 60 and 240 μM Cu, respectively. Pathway enrichment analysis revealed that high Cu led to disturbances of glutathione metabolism, nucleotide metabolism, glycerophospholipid and ether lipid metabolism. Using cell biological assays, we found that exposure to high Cu significantly decreased the GSH/GSSG ratio and altered the activities of the antioxidant enzymes SOD and CAT. Exposure to high Cu significantly increased the level of mitochondrial ROS. These findings further supported the results revealed by metabolomic analysis and provided clues for elucidating the mechanism by which Cu interferes with the development of ovarian follicles.

Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line.

Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N1,N11-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography-mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells.

Relationship between systemic biomarker of lipid peroxidation 4-hydroxynonenal and lipidomic profile of morbidly obese patients undergoing bariatric surgery

Obesity is characterized by fat accumulation, impaired metabolism and oxidative stress, frequently associated with lipid peroxidation and generation of bioactive 4-hydroxynonenal (4-HNE). This study aimed to evaluate the impact of bariatric surgery-induced weight loss on lipid peroxidation and associated perturbations in lipid profile. Plasma samples of twenty obese individuals before and 6 months after bariatric surgery were collected in addition to samples of ten healthy controls. HILIC-LC-MS/MS platform was used to characterize phospholipid profile, while lipid peroxidation markers 15-F2t-IsoP, 10-F4t-NeuroP and reactive aldehyde 4-HNE were quantified by RP-LC-MS/MS and GC-MS, respectively. Six months post-surgery lipid peroxidation markers decreased significantly and the BMI of morbidly obese patients decreased by 13 on average. Lipidomics analysis, identified 117 phospholipid species from seven classes, and showed obesity-associated lipidome perturbations, particularly in ether-linked phosphatidylethanolamines (PEo). A total of 45 lipid species were found to be significantly altered with obesity, while 10 lipid species correlated with lipid peroxidation markers. Sample pairwise analyses indicated an interesting link between 4-HNE and the amount of two PEos, PEo (38:2) and PEo (36:2). The results indicate that weight loss-induced improvement of redox homeostasis together with changes in lipid metabolites may serve as markers of metabolic improvement. However, further studies are needed to understand the role of obesity-induced oxidative stress on ether lipid biosynthesis and lipidome perturbations, as well as the impact of bariatric surgery on metabolic improvement.

Study based on metabolomics and network pharmacology to explore the mechanism of Ginseng-Douch compound fermentation products in the treatment of hyperlipidemia.

Ginseng-Douchi (GD) is a complex fermented product of ginseng and soybean, similar to natto, and is effective in the treatment of hyperlipidemia, but the mechanism of action involved needs to be further explored. The present study combines a comprehensive strategy of network pharmacology and metabolomics to explore the lipid-lowering mechanism of GD. First, a hyperlipidemia rats model induced by a high-fat diet was established to evaluate the therapeutic effects of GD. Second, potential biomarkers were identified using serum metabolomics and metabolic pathway analysis was performed with MetaboAnalyst. Third, network pharmacology is used to find potential therapeutic targets based on the blood-influencing components of GD. Finally, core targets were obtained through a target-metabolite and the enrichment analysis of biomarkers-genes. Biochemistry analysis showed that GD exerted hypolipidemic effects on hyperlipidemic rats. Nineteen potential biomarkers for the GD treatment of hyperlipidemia were identified by metabolomics, which was mainly involved in linoleic acid metabolism, glycerophospholipid metabolism, ether lipid metabolism, alpha-linolenic acid metabolism and glycosylphosphatidylinositol-anchor biosynthesis. GD had a callback function for ether lipid metabolism and glycerophospholipid metabolism pathways. Eighteen blood components were identified in serum, associated with 85 potential therapeutic targets. The joint analysis showed that three core therapeutic targets were regulated by GD, including PIK3CA, AKT1 and EGFR. This study combines serum medicinal chemistry of traditional Chinese medicine, network pharmacology and metabolomics to reveal the regulatory mechanism of GD on hyperlipidemia. © 2024 Society of Chemical Industry.

Environmental Temperature Variation Affects Brain Lipid Composition in Adult Zebrafish (Danio rerio).

This study delves deeper into the impact of environmental temperature variations on the nervous system in teleost fish. Previous research has demonstrated that exposing adult zebrafish (Danio rerio) to 18 °C and 34 °C for 4 or 21 days induces behavioural changes compared to fish kept at a control temperature of 26 °C, suggesting alterations in the nervous system. Subsequent studies revealed that these temperature conditions also modify brain protein expression, indicating potential neurotoxic effects. The primary aim of this work was to investigate the effects of prolonged exposure (21 days) to 18 °C or 34 °C on the brain lipidomes of adult zebrafish compared to a control temperature. Analysis of the brain lipidome highlighted significant alteration in the relative abundances of specific lipid molecules at 18 °C and 34 °C, confirming distinct effects induced by both tested temperatures. Exposure to 18 °C resulted in an increase in levels of phospholipids, such as phosphatidylethanolamine, alongside a general reduction in levels of sphingolipids, including sphingomyelin. Conversely, exposure to 34 °C produced more pronounced effects, with increases in levels of phosphatidylethanolamine and those of various sphingolipids such as ceramide, gangliosides, and sphingomyelin, alongside a reduction in levels of ether phospholipids, including lysophosphatidylethanolamine ether, phosphatidylethanolamine ether, and phosphatidylglycerol ether, as well as levels of glycolipids like monogalactosyldiacylglycerol. These results, when integrated with existing proteomic and behavioural data, offer new insights into the effects of thermal variations on the nervous system in teleost fish. Specifically, our proteomic and lipidomic findings suggest that elevated temperatures may disrupt mitochondrial function, increase neuronal susceptibility to oxidative stress and cytotoxicity, alter axonal myelination, impair nerve impulse transmission, hinder synapse function and neurotransmitter release, and potentially lead to increased neuronal death. These findings are particularly relevant in the fields of cell biology, neurobiology, and ecotoxicology, especially in the context of global warming.